Processes for the selective amination of ketomorphinans

Abstract

The present invention is generally directed to a process for the preparation of a ketomorphinan comprising maintaining a ketone group as unprotected and performing reductive amination using a hydrogen source and a catalyst.

1. A process for the preparation of a N-alkylated ketomorphinan compound of Formula (IV): 
       
         
           
           
               
               
           
         
       
       the process comprising:
 maintaining a ketone group of a N-imine ketomorphinan or hemiaminal ketomorphinan as unprotected; and, reducing the N-imine ketomorphinan or hemiaminal ketomorphinan in the presence of a hydrogen source and a catalyst without substantially reducing the 6-keto functionality to an alcohol, the N-imine ketomorphinan or hemiaminal ketomorphinan compound of Formula (III): 
 
       
         
           
           
               
               
           
         
         wherein:
 R 1 , and R 2  are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, and {—}OR 15 ; 
 R 3 , R 7 , and R 8  are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and {—}OR 15 ; 
 R 9  is selected from the group consisting of hydrogen, acyl, hydrocarbyl, substituted hydrocarbyl, and heterocyclo; 
 R 14  is selected from the group consisting of hydrogen and hydroxy; 
 R 15  is selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and a hydroxy protecting group; 
 X is oxygen; 
 Z 1  is selected from the group consisting of {—}NCH(OH)(R 9 ), and {—}N + ═CH(R 9 ); and 
 Z 2  is {—}NCH 2 R 9 . 
 
       
     
     
       2. The process of  claim 1 , wherein the N-imine ketomorphinan or hemiaminal ketomorphinan is formed by reacting an aldehyde comprising the formula R 9 CHO with a 6-ketonormorphinan compound of the following structure: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1 , and R 2  are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, and {—}OR 15 ; 
         R 3 , R 7 , and R 8  are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and {—}OR 15 ; 
         R 9  is selected from the group consisting of hydrogen, acyl, hydrocarbyl, substituted hydrocarbyl, and heterocyclo; 
         R 14  is selected from the group consisting of hydrogen and hydroxy; 
         R 15  is selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and a hydroxy protecting group; 
         Z 0  is selected from the group consisting of hydrogen; and 
         X is oxygen. 
       
     
     
       3. The process of  claim 2 , wherein the aldehyde is selected from the group consisting of formaldehyde, acetaldehyde, cyclopropanecarboxaldehyde,
 cyclobutanecarboxaldehyde, benzaldehyde, substituted benzaldehyde, and a combination thereof; the 6-ketonormorphinan is selected from the group consisting of noroxymorphone, noroxycodone, norhydrocodone, northebaine, nororipavine, and norhydromorphone; and the N-alkylated ketomorphinan compound of Formula (IV) is selected from the group consisting of nalbuphone, naltrexone, naloxone, and a combination thereof. 
 
     
     
       4. The process of  claim 3 , wherein the amount of aldehyde is from about 1.0 to about 3.0 equivalents per equivalent of the 6-ketonormorphinan; and the reaction of the aldehyde and the 6-ketonormorphinan occurs within a temperature range from about 20° C. to about 60° C. and in the presence of a solvent system comprising an organic solvent. 
     
     
       5. The process of  claim 4 , wherein the organic solvent is selected from the group consisting of methanol, ethanol, isopropanol, n-propanol, n-butanol, acetonitrile, tetrahydrofuran, ethyl ether, dimethylformamide, dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide, ethyl acetate, propyl acetate, and a combination thereof. 
     
     
       6. The process of  claim 1 , wherein the ketone functionality within the ketomorphinan is reduced less than about 5%. 
     
     
       7. The process of  claim 1 , wherein the hydrogen source comprises a protic compound selected from the group consisting of formic acid, organic or inorganic salts of formic acid, isopropanol, n-propanol, n-butanol, and a combination thereof; and the catalyst comprises ruthenium, rhodium, or iridium. 
     
     
       8. The process of  claim 1 , wherein the hydrogen source is formic acid; and the catalyst is selected from the group consisting of dichloro(arene)Ru(II) dimer, dichloro(pentamethylcyclopentadienyl)Rh(II) dimer, BINAP-Ru (II) diacetate, BINAP-Ru (II) dichloride, BINAP-Ru (II) dibromide, BINAP-Ru (II) diiodide, [RuCI((R or S)BINAP)(C 6 H 6 )]Cl, dichloro(pentamethylcyclopentadienyl)iridium (III) dimer, Ru(III) chloride, RuCl 3 hydrate, Ru(III) acetylacetonate, tetraalkylammonium RuCI 4 , and pyridinium RuCI 4 . 
     
     
       9. The process of  claim 1 , wherein the optical activity of the N-alkylated ketomorphinan compound of Formula (IV) is selected from the group consisting of (+), (−), and a combination thereof; and the configuration of the chiral carbons C-5, C-13, C-14, and C-9 of the N-alkylated ketomorphinan compound of Formula (IV) may be selected from the group consisting of RRRR, RRSR, RRRS, RRSS, RSRR, RSSR, RSRS, RSSS, SRRR, SRSR, SRRS, SRSS, SSRR, SSSR, SSRS, and SSSS; provided, however, that the C-15 and the C-16 carbons are both either on the alpha face of the molecule or the beta face of the molecule. 
     
     
       10. The process of  claim 1 , wherein the N-imine or hemiaminal ketomorphinan compound of Formula (III)is an analog of noroxymorphone; the catalyst comprises a di- μ-chlorobis (ruthenium)(II) dimer; and, the hydrogen source comprises formic acid or a formic acid salt. 
     
     
       11. The process of  claim 10 , further comprising producing the ketomorphinan of Formula (IV) in greater than 85% yield.